Cancers are generally treated with various forms of cytoreductive therapies. Cytoreductive therapies involve administration of ionizing radiation or chemical toxins which are cytotoxic for rapidly dividing cells. Side effects of such therapy can be attributed to cytotoxic effects upon normal cells and can usually limit the use of cytoreductive therapies. A frequent side effect is myelosuppression, or damage to bone marrow cells which gives rise to white and red blood cells and platelets. As a result of myelosuppression, patients develop cytopenia which are blood cell deficits. As a result of cytopenias, patients are exposed to increased risk of infection and bleeding disorders.
Cytopenia is a major factor contributing to morbidity, mortality, and under-dosing in cancer treatment. Many clinical investigators have manipulated cytoreductive therapy dosing regimens and schedules to increase dosing for cancer therapy, while limiting damage to bone marrow. One approach involves bone marrow transplantations in which bone marrow hematopoietic progenitor cells are removed before a cytoreductive therapy and then reinfused following therapy to rescue bone marrow from toxicity resulting from the cytoreductive therapy. Progenitor cells may implant in bone marrow and differentiate into mature blood cells to supplement reduced population of mature blood cells.
High-dose chemotherapy is therapeutically beneficial because it can produce an increased frequency of objective response in patients with metastatic cancers, particularly breast cancer, when compared to standard dose therapy. This can result in extended disease-free remission for some even poor-prognosis patients. Nevertheless, high-dose chemotherapy is toxic and many resulting clinical complications are related to infections, bleeding disorders and other effects associated with prolonged periods of myelosuppression.
Currently, a human recombinant granulocyte macrophage-colony stimulating factor (GM-CSF) analog protein (sargramostim) is available in the U.S. for accelerating hematopoietic recovery following bone marrow transplantation. Sargramostim treatment has resulted in a reduction of many complications associated with bone marrow transplantation.
The existence of both marrow borne and circulating hematopoietic stem cells has been demonstrated using a variety of experimental studies and cell culture techniques. Two colony stimulating factors, GM-CSF and granulocyte colony stimulating factor (G-CSF), have been shown to increase the frequency of circulating hematopoietic progenitor or stem cells. Several studies (Gianni et al., Lancet 334:589 (1989); Siena et al., Blood 74:1905 (1989); and Molineux et al., Blood 76:2153 (1990)) describe in vivo administration of GM-CSF to increase the transplantation potential and frequency of primitive progenitor cells in a population of peripheral blood cells obtained from patients with tumors. These procedures represent attempts to rescue chemotherapy-induced suppresion of bone marrow by administering GM-CSF in vivo to recruit bone marrow progenitor cells into peripheral blood and then later administering harvested hematopoietic progenitor cells to patients.
More specifically, Gianni et al. describe a clinical study in which patients received high dose cyclophosphamide (7 g/m.sup.2) and were transplanted with autologous peripheral blood progenitor cells and autologous bone marrow cells. Patients who were treated with GM-CSF as a progenitor cell recruitment agent, prior to harvesting peripheral blood progenitor cells, recovered more quickly from cytopenia than patients whose peripheral blood progenitor cells were not recruited by GM-CSF. Thus GM-CSF administration increased the number of peripheral blood progenitor cells. This protocol resulted in more rapid hematopoietic recovery in tested patients than in control patients who received chemotherapy without autologous bone marrow transplantation but with peripheral blood progenitor cell support.
Cancer patients treated with high dose chemotherapy and autologous bone marrow transplantation who received subsequent GM-CSF treatment have shown faster myeloid recovery than similarly treated historical controls (Brandt et al., N. Engl. J. Med. 318:869 (1988) and Nemunatis et al., Blood 72:834 (1988)). Studies have shown that the time to achieve a minimum granulocyte count of 0.5.times.10.sup.9 /l after cytoreductive therapy was shorter in patients receiving GM-CSF. Granulocyte count increases were most pronounced during GM-CSF infusion. After discontinuation of GM-CSF, leukocyte counts in treated patients fell to control levels (Brandt et al., supra).
GM-CSF is also useful for autologous bone marrow transplantation following cytoreductive therapy. Socinski et al., Lancet 331:194 (1988) reported that GM-CSF administration after cytotoxic chemotherapy expands a circulating pool of hematopoietic progenitor cells by approximately 60-fold. Others have reported that human mononuclear cells circulating in the circulating blood, particularly during recovery from chemotherapy-induced myelosuppression, have been used to successfully reconstitute hematopoiesis after fully myeloablative (complete bone marrow toxicity) treatments (See, e.g., Bell et al., Hematol, Oncol.5:45 (1987)).
Mason et al., Proc. Amer. Assoc. Cancer Res. 32:193 (1991), reported that in vitro interleukin-3 (IL-3) alone or in combination with interleukin-6 (IL-6) increased the number of colony forming progenitors from human blood progenitor cells two fold in vitro. Mason et al. also reported that GM-CSF did not expand the colony forming progenitor population in vitro. Accordingly, autologous hematopoietic cell transplantation has proven to be a valuable technique to speed recovery from cytoreductive therapies. Improvements in autologous hematopoietic cell transplantation can further speed recovery from cytoreductive therapies and even allow the use of higher and more effective doses in cytoreductive therapies. This invention provides an improvement in autologous hematopoietic cell transplantation.